Biology subjects

Malhotra, L.

Publications and source records attributed to Malhotra, L..

3 recordsLinked to original sources

bioRxiv2025

Immunogenicity and Structural Features of a Stabilized Clade-C HIV-1 Env Derived from a Pediatric Elite-neutralizer

The envelope (Env) glycoprotein derived from circulating viruses in elite-neutralizers (who naturally develop broadly neutralizing antibodies (bNAbs)), serves as potential template for HIV-1 vaccine design. Herein, we report the structure and immunogenicity of soluble clade-C HIV-1 Env trimer (330) derived from a pediatric elite-neutralizer (AIIMS_330). Using SOSIP, NFL and ferritin-nanoparticle (NP) platforms, we engineered immunogens that preserved native-like Env conformation, exhibited high thermostability and nanomolar affinity for diverse bNAbs, with minimal reactivity to non-neutralizing antibodies. Cryo-EM structure solved at 5 [A] resolution of 330-SOSIP trimer-autologous bNAb 44m complex revealed interactions at GDIR motif, N332 supersite along with additional contacts at E293, K337, K446 and glycans N326, N442, N448, as compared to our previously reported BG505-44m structure. Rabbit immunizations with soluble and NP-displayed formats elicited autologous, and heterologous neutralization of tier-1 clade-C viruses. Herein we define a structurally resolved HIV-1 clade C Env that supports multivalent vaccine strategies and provides mechanistic insights toward rational HIV-1 immunogen design.

immunology↗

bioRxiv2025

Hypoxia-Mediated Molecular Interactions of Tissue-Specific Mesenchymal Stem Cells Drive Metabolic Reprogramming and Immunomodulation in Acute Graft-versus-Host Disease

BackgroundMesenchymal stem cells (MSCs) mediate immunomodulation through various mechanisms, including apoptosis, efferocytosis, and mitochondrial transfer. Our study investigates the impact of hypoxia preconditioning on the immune metabolic reprogramming and immunomodulatory potential of MSCs in acute graft-versus-host disease (aGVHD). Additionally, we explored the differential immunomodulatory effects of tissue-specific MSCs, specifically bone marrow (BM) and Whartons Jelly (WJ), and elucidated the mechanisms underlying variability in their therapeutic efficacy. MethodsMSCs were isolated from BM and WJ and subjected to hypoxia preconditioning. Their immunometabolic programming potential was assessed by evaluating T-cell proliferation, regulatory T-cell (Treg) induction, effector T-cell differentiation toward Th2, Th9 phenotypes, and macrophage polarization, T-cell bioenergetics in the direct co-culture systems. ResultsWJ-MSCsHYP exhibited superior immunomodulatory properties compared to BM-MSCsHYP, by inhibiting T-cell proliferation, enhancing Treg induction, and promoting anti-inflammatory macrophage polarization. WJ-MSCsHYP demonstrated enhanced mitochondrial transfer to T-cell, improving mitochondrial health, reducing ROS, and promoting oxidative phosphorylation, leading to immune homeostasis. Unlike BM-MSCs, WJ-MSCs exhibited higher rates of apoptosis, which facilitated immune modulation through mechanisms independent of efferocytosis. ConclusionOur findings highlight that WJ-MSCsHYP is a superior candidate for aGVHD by utilizing apoptosis, mitochondrial transfer, and metabolic reprogramming to achieve immune regulation.

immunology↗

bioRxiv2023

Phenotypical mapping of TP53 unique missense mutations spectrum in human cancers

The p53 tumor suppressor is one of the most mutated genes responsible for tumorigenesis in most human cancers. Out of 29,891 genomic mutations reported in the TP53 Database (https://tp53.isb-cgc.org/), 1297 are identified as unique missense somatic mutants excluding frameshift, intronic, deletion, nonsense, silent, splice and other unknown mutations. we have comprehensively analyzed all these 1297 unique missense mutations and created a phenotypical map based on the distribution of mutants in each domain, the functional state of the protein, and their occurrence in different types of tissues and organs. Our mutation map shows that almost 118 unique missense mutants are reported in the transactivation domain (TADs) and proline-rich domain (PRR), 1,065 in the central DNA-binding domain (DBD), and 113 in the oligomerization (OD) and regulatory domain (RD). Based on the phenotype these 1297 mutations are subdivided into 46 super trans, 491 functional, 315 partially functional, and 415 non-functional mutants. The prevalence of all these mutations was checked in 71 different types of tissues and found the mutant R248Q is reported in 51 types of tissues followed by R175H and R273H in 46 types. The propensity calculation of mutation for each amino acid in p53, showed Proline, Arginine, and Leucine/Glutamic acid are the most frequently mutated residues in the TAD domain, DBD, and TD respectively. We have correlated the impact of these mutations in the structure and function of p53 and highlighted the TP53 unique missense mutants that can be a potential therapeutic drug target with tremendous clinical applications.

cancer biology↗